Solid tumors exist in a stressed environment for cell growth. As even the smallest tumors grow they rapidly outstrip new blood vessel formation leading to poor perfusion and hypoxia. Genes induced by hypoxia allow the cancer cell to adapt to the hostile hypoxic environment by switching to anaerobic metabolism, decreasing overall protein synthesis, causing resistance to cell death, producing factors that increase the formation of new blood vessels from the existing vasculature (angiogenesis), and increased metastasis. Tumor cells also frequently develop constitutive upregulation of genes that regulate the hypoxic stress response. These constitutive and adaptive changes make tumors aggressive, resistant to radiation and chemotherapy, and lead to a poor patient prognosis. The hypoxic stress response is a normal physiological process employed in the early stages of embryogenesis but with a limited role in well perfused normal adult tissues. Although the changes result in aggressive, drug-resistant tumors they also provide an Achilles heel for selectively attacking the tumor, because without them the cancer cells will die. Thus, the hypothesis upon which our studies are based is that understanding the pathways that regulate the tumor's response to the stress of hypoxia and the consequences this has for tumor growth, will provide novel targets and the development of agents to selectively treat cancer. The most studied mechanism mediating the cancer cell's response to hypoxia is an increase in the levels of the hypoxia inducible factor-1 (HIF-11) transcription factor. We provide evidence for a new pathway of HIF-11 regulation by the endoplasmic reticulum (ER) unfolded protein response (UPR) that mediates the synthesis of HIF-11 and other stress proteins in hypoxia. We have also identified a novel oxygen independent pathway for HIF-11 degradation mediated by HAF/SART-1 which we have shown to be a novel E3 ubiquitin ligase for HIF-11. We will investigate the mechanisms and regulation of the HAF/SART-1-induced degradation of HIF-11 to provide novel targets for therapeutic intervention. There is ample clinical and experimental evidence for a HIF-11 independent mechanism for maintaining tumor growth in hypoxia. It is known that despite a general inhibition of protein translation during hypoxia the synthesis of HIF-11 and of other stress survival proteins is maintained or even increased. Understanding this mechanism could provide novel drug targets to inhibit the tumor's survival response to hypoxia. The overall goal of our studies is to understand mechanisms that contribute to the maintenance of tumor growth in hypoxia, involving both HIF-11 and other stress proteins that will provide new drug targets and therapeutic strategies for treating cancer. PUBLIC HEALTH RELEVANCE: Hypoxic stress is a feature of all tumors as they grow and outstrip new blood vessel growth, but is not seen in most normal tissues. Tumors have developed mechanisms that allow them to grow in hypoxia, thus, providing an Achilles heel for selectively attacking the tumor. The goal of our studies is to understand these mechanisms in order to provide targets for the development of new types of cancer drugs and strategies for treating cancer